Novel process for preparing heterocyclic compounds



utilities known to the art.

United States Patent 3,164,596 NQVEL PRQQESS FOR PRERARKNG HETERG- (IYCLEQ COMPGUNDS Irwin J. Pachter, Erdenheim, Pa, assignor to Emith Kline 8; French Laboratories, Philadelphia, Pa, a corporation of Pennsylvania No Drawing. Filed Feb. 13, 1962, Ser. No. 172,838

8 Claims. (Cl. 266-2515) This invention relates to a novel process for preparing heterocyclic compounds possessing as an essential part of their nucleus a condensed aromatic Z-aminopyrazine structure. More precisely the heterocyclic compounds produced by the process of this invention have the following basic structure:

(VII) amino, lower alkylamino, diloweralkylamino, lower alkylthio, lower alkoxy, heterocyclic amino, alkyl, phenyl, thienyl, etc. groups. Such substitution will be made as desired by one skilled in the art using known synthetic methods to obtain compounds whose generic classes have These substituents do not affect the novel reaction of this invention except as described hereafter.

The term R denotes an alkyl or aryl moiety having a maximum of 12 carbon atoms. Exemplary of such groups are lower alkyl, cycloalkyl for. instance cyclohexyl or cyclopentyl, phenyl, thienyl, lower alkoxy, phenoxy or carbamyl. The chemical character of R must be such that it is stable toward elimination during the cyclization step of the reaction. For example it has been found that when R is an aryl mercapto or lower alkyl mercapto moiety it is eliminated during cyclization to give the 2- acyl heterocyclic compound rather than the Z-mercapto derivatives.

The process of this invention has made possible production of heterocyclic compounds as discussed above in good yield and using nitrosoamines with easily prepared substituted ketones have a reactive OC-HlfithYlCIlfi moiety.

The compounds produced by the process of this invention have various utilities. Most universal is their use in known reactions as intermediates for preparing medicinally active compounds. Many of the compounds, such as those in which X is phenylene or naphthylidene, have utility as nuclei for preparing dyestuffs or for their own inherent fluorescent or dyestuft character. products, such as those in which X is pyridinediyl or, especially pyrimidinediyl, have activity in themselves as medicinal agents such as diuretics, :antihypertensives, vasodilators for instance coronary arterial ,dilators, antibacterials, anti-folio acid compounds or microorganism antagonists such as anti-Lactobacillus casei, Streptococcus faecalis, Staphyloccous aurcus or Escherichia coli agents,

While the nature of the products produced by the process of this invention is not particularly dependent on the nature of the X ring or its substituents the full scope Other 3,164,596 Patented Jan. 5, 1965 2. of this invention will be illustrated by concentrating illustrative examples in the pteridine series whose end products are known to have anti-folic acid or diuretic/ antihypertensive activities. Similar reactions in various series containing other nuclei will be apparent from the examples provided.

The process of this invention comprises reacting an o-nitrosoamine (II) with an acylmethylene compound (I) in the presence of cyanide ions, preferably in excess, to give the desired Z-aminopyrazino heterocyclic end product (VII). It is believed that this novel process proceeds as follows:

is eliminated during the reaction, the specific character of the R group is unimportant other than being readily available, chemically stable under the reaction conditions and sufliciently activating to make the adjacent methylene moiety reactive as described hereafter. One skilled in the art willrecognize that the initial condensation of the (pt-methylene group of I with the nitroso radical of II will only occur it the methylene group is sufficiently activated. For example the starting materials represented by I are only operative if R is an electron withdrawing moiety such as an aryl group or carbamyl. The reaction will not work to high yields when R is lower alkyl, alkoxy, phenoxy or cycloalkyl. These compounds are prepared by a variation of this reaction as described below.

The novel aspects of this process apparently involve a novel autoxidation step, probably from the dihydronitrone (III) to the nitrous (IV), coupled with a novel cyclization with elimination of an acyl moiety as the carboxylic acid.

The nitrone type intermediates are not usually isolated in the reaction but the Z-aminopyrazine heterocycle end product is immediately isolated in acceptable purity and isease nitroso group because of the electropositive nature of the amine substituent. This effect can be compensated by using an electronegative moiety for R in the acylmethylene compound (I) such as p-nitrophenyl, methoxy or carbomethoxy. While very high yields are realized using strongly electronegative groups at, either R or R or both, the reaction is operative under forcing conditions when electropositive groups are present such as amino for R in structure X. Similar effects when described fully as hereabove will be apparent to one skilled in the art who can chose the desired reactants to prepare the sought M Z-aminopyrazine heterocycles in the best possible yield.

Substantially equimolar quantities of the acylmethylene derivative (I) and the o-nitrosoamine (II) are reacted in a solvent in which the reactants are substantially soluble such as in a lower alkanol preferably ethanol, isopropanlol or methanol, N,Ndimethylf0rmamide, N,N-dimethylacetamide, aqueous mixtures thereof or the like. At least one molar equivalent of cyanide ions is essentially present but preferably an excess is used. An alkali metal cyanide ideally furnishes the desired cyanide ions. Sodium or potassium cyanides are most commonly used. The reaction is usually run at elevated temperatures for instance at from about 65 C. to the reflux temperature of the reaction mixture for from about /2 to about 24 hours. The preferred conditions are in methanol or ethanol solvent or aqueous mixtures thereof at reflux with an excess of cyanide ions for from about /2 to 16 hours. Other conditions have not been found to marked advantage except as described hereafter.

The starting materials are in all cases readily known and available or prepared by known methods. The o-nitrosoamines, for example, are generally prepared by 'nitro'sating the amine. For example, see US. Pat. Nos. 2,963,481, 2,975,180, 2,963,479 and 2,963,478. It will also be apparent tov one skilled in the art that in the phenyl and pyridylseries of'starting materials simple unsubstituted o-nitrosoamines cannot be preparedeither due to the lack of reactivity toward nitrosation of the aromatic nucleus or self-condensation. Nlitrosoamines in these series necessarily must have another activating moiety such as an amino or hydroxyl group present. Exemplary of such available nitrosoamino starting materials are 2,4- diarnino-l-nitrosobenzene, 2,4-diamino-5-methyl-l-nitrosobenzene, 2-amino-l-nitrosonaphthalene, l-amino-Z-nitrosonaphthalene all of which give 2-amino-pyrazine containing heterocycles having carcinogenic properties or having utility as dyestuif intermediates. A discussion of nitrosation of pyridines may be found in Heterocyclic Compounds, 14 II 481. In the preferred pyrimidine series the nitroso compounds are all readily prepared.

The acylmethylene compounds of Formula I are well known ketones which have essentially an oc-Substiitt6nt R which prevents elimination of water rather than an acyl moiety during cyclization (VIV).' It is an outstanding advantage of this process that the reaction uses a readily available ketone rather than an acylmethylene cyanide. Further details will be apparent from the ex- .amples.

A preferred and advantageous modification of the proc ess of this invention is to form a pyridinium salt derivative of the acylmethylene derivative to be used as starting material. The use of a pyridinium salt derivative allows the formation of the nitrone intermediate by an elimination reaction without going through the rather slow autoxidation step. This preferred modification activates the methylene group of I and enables use of starting materials of the full scope and the previous definition of R. The

reaction sequence of the aspect of the invention may be postulated as follows:

In this reaction sequence R, R and X are as described hereabove with the additional proviso that none of the substituted moieties react with, or interfere with the formation of, the pyradinium intermediate (VIII); Py is any basic tertiary organic base capable of forming quaternary salts particularly the preferred pyridinium or those moieties derived from pyridine especially the'lower alkyl substituted compounds such as picolinium, lutidinium, methylethylpyridinium, etc.; and Z is an anion capable of forming such a pyridinium salt, preferably chloride, bromide or iodide. I

in practice a strongly activating group at R such as carbamyl may induce elimination of the R CO- moiety in situ before initial condensation of the pyridinium intermediate (Vlll). The reaction conditions of this invention are identical to those described herebefore. The pyridinium starting materials (Vlll) are Well known to the art. Their preparation consists generally of monohalogenation of the acylmethylene parent (I) followed by reaction with an excess of the pyridine compound.

It has been found thatreaction of the pyridinium salt '(Vlll) as starting material with the nitrosoamine is very fast and is carried out in very high yield. While the 'parent reaction initially described herein usually must undergo reaction for several hours for complete reaction,

the pyridinium reaction is often substantially complete in a few minutes and with little heat-ing such as at room temperature or with gentle heat. Ideally reaction conditions are up to 6 hours in duration at from about 25- or I k/N NO- R i r \N/ in which R, R Py and Z are defined as above;

R is aryl, amino, loweralkylamino, diloweralkylamino, cyclic amino such as piperidinyl, alkyl, hydrogen, hydroxy or alkylthio, all having a maximum of 8 carbon atoms.

8 1 The preferred groups are phenyl, amino or lower alkylthio. The latter moiety is particularly useful as an intermediate for preparing the Z-amino derivatives by condensation with an excess of the desired amine such as ammonia with advanced temperatures in a closed system if necessary;

R is an amino, loweralkylarnino, diloweralkylamino,

.hydrogen, cyclic amino-such as pipcridino, alkyl, hydroxy .m -I- a.

. at reflux for one hour.

1: =3 carried out under the same reaction conditions as described above.

The following terms as used therein and in the claims are defined as follows:

Lower alkanola straight or branched chain aliphatic alcohol having 1-6, preferably l-3, carbon atoms. Methanol, ethanol or isopropanol are preferred. 1

Alkyl-straight or branched alkyl or cycloalkyl ha ing a maximum of 8 carbon atoms.

Lower alkylstraight or branched alkane having 1-6 carbon atoms, preferably 1-3.

Aryl-a cyclic organic residue containing only carbon, mono-sulfur, nitrogen or mono-oxygen as ring members of an aromatic system having a total maximum of 8 carbon atoms. The aromatic ring system may be substituted in Well known inert substituents often referred to as garbage radicals which are nontoxic such as halogen, methyl, methoxy, trifluoromethyl, etc. Phenyl or thienyl are preferred.

Lower alkoxystraight or branched alkyloxy having 1-6 carbon atoms, preferably 1-3.

Alkali meta1as commonly defined in the art with sodium, potassium or calcium cations preferred.

The following examples will make use of the process of this invention apparent to one skilled in the art and should not be construed as limiting the scope of this invention thereto.

Example 1 A mixture of 1.63 g. (0.01 mole) of benzoylacetamide, 1.0 g. (0.005 mole of 4,6-diamino-S-nitroso-Z-phenylpyrimidine, 0.5 g. (0.01 mole) of sodium cyanide, ml. of water and 40 ml. of ethanol is heated at reflux for 3 hours. Cooling gives 4,7-diamino-2-phenyl-6-pteridinecarboxamide.

Example 2 A mixture of 1.1 g. of 4,G-diamino-2-phenyl-5-nitrosopyrimidine, 0.5 g. of sodium cyanide, 2.0 ml. of phenylacetone, 5 ml. of water and ml. of ethanol is heated The desired 4,7-diamino-2,6-diphenylpteridine separates during the heating and is isolated by cooling and filtration.

Example 3 A mixture of 2.4 g. of a-benzoyl-bromoacetamide, 2 ml. of pyridine and ml. of absolute ethanol is heated briefly then added to a mixture of 1.2 g. of 4,6-diamino 5-ni troso-2-phenylpyrimidine, 0.5 g. of sodium cyanide, 10 ml. of water and 50 ml. of ethanol. Warming on a hot plate causes instantaneous reaction giving yellow crystals of 4,7-diamino-2-phenyl-6-pteridinecarboxamide.

Example 4 A mixture of 1 g. of propiophenone-a-pyridinium bromide (prepared from the halide by reaction with an excess of pyridine in alcohol), 0.3 g. of 4,6-diamino-5-nitroso-2- phenylpyrimidine, 0.19 g. of sodium cyanide and 20 ml. of aqueous methanol is heated at reflux for 4 hours. Cooling and concentration gives the desired 4,7-diamino-2- phenyl-6-methylpteridine.

Example 5 A mixture of 2.5 g. of ethyl a-bromo-phenylacetate, 2 ml. of lutidine and 50 ml. of methanol is warmed, then added to a warmed mixture of 1.6 g. of 2,4,6-triamino-5- nitrosopyrimidine, 0.7 g. of potassium cyanide and 50 ml. of aqueous isopropanol. The mixture is then heated at reflux for 48 hours. Evaporation, cooling and fractional crystallization gives 2,4,7-triamino-6-phenylpteridine.

Example 6 A mixture of 2.5 g. of ethyl B-arketo-fl-phenylpropionate is reacted with 1.5 g. of 2-methylthio-4,6-diamino-5- nitrosopyrimidine, 0.8 g. of sodium cyanide in ml. of aqueous ethanol at reflux for 12 hours. Working up as 6 described above gives 2-methylthio-4,7-diamino-6-phenylpteridine.

Example 7 A mixture of 4 g. of a-phenoxyacetophenone-a-pyridinium bromide (prepared as in Example 3), 2 g. of 4,6- diamino-2-methyl-5-nitrosopyrimidine and 1.2 g. of sodium cyanide in 75 m1. of aqueous ethanol is heated at reflux for one hour and cooled to give 4,7-diamino-6- phenoxy-Z-methylpteridine.

Example 8 A solution of 2.3 g. of ethyl cyclohexylacetate in chloroform is brominated with one molar equivalent of bromine and converted to the methylethylpyridinium salt as in Example 3. The salt (12 g.) is reacted with 0.8 g. of 4,6- diamino-5-nitrosopyrimidine and 0.5 g. of sodium cyanide in aqueous ethanol for 16 hours to give 4,7-diamino-6- cyclohexylpteridine.

Example 9 A mixture of 3.2 g. of 3-nitroso-2,6-diamino-pyridine, 1 g. of sodium cyanide, 3 ml. of phenylacetone and 50 ml. of aqueous ethanol is heated at reflux for 12 hours then cooled to give the desired 2,7-diamino-3-phenylpyridopyrazine.

Example 10 A mixture of 1.5 g. of 2,4-diamino-l-nitroso-benzene, 2.3 g. of desoxybenzoin, 1 g. of sodium cyanide in ml. of aqueous ethanol is heated at reflux for 12 hours. Cooling separates 2,7-diamino-3-phenylquinoxaline.

Example 11 A mixture of 1.2 g. of 2-amino-l-nitroso-naphthalene, 1.5 g. of propiophenone-a-pyridinium bromide (Example 1) and 0.2 g. of sodium cyanide in aqueous methanol are reacted as in Example 4 to give 2-amino-3-methylbenzquinoxaline.

Example 12 Substituting the following reactants for those corresponding in either Example 1 or Example 3 in molar equivalents gives the following:

4,6-diamino-S-nitroso-2-hydroxypyrimidine plus p-nitropropionphenone-a-pyridinium bromide (prepared as in Example 4) gives 2-hydroxy-4,7-diamino-6-methylpteridine;

4,6 diamino 5-nitroso-2-(fi-thienyl)-pyrimidine plus benzoylacetamide gives 4,7-diamino-2-(B-thienyl)-6- pteridinecarboxamide;

4,6-diamino-5-nitroso-2-phenylpyrimidine plus a-benzylacetophenone-a-pyridinium bromide (the bromo compound of which may be prepared by a Friedel-Crafts reaction using benzene and w-phenyl-a-bromo-propionylbromide) gives 4,7-diamino-6-benzyl-2-phenylpteridine;

4,6-diamino5-nitroso-2-(p-tolyl)-pyrimidine plus benzoylacetamide gives 4,7-diamino-2-(p-tolyl)-6-pteridinecarboxamide;

6 amino 4-methylamino-5-nitroso-2-phenylpyrimidine plus a-benzoylacetamide-a-pyridinium bromide gives 7- amino-4-methylamino-2-phenyl-6-pteridine-carboxamide;

2-amino-3-nitroso-6-hydroxypyridine plus phenylacetone gives 2-amino-3-phenyl-7-hydroxypyridopyrazine.

2,4-diamino-5-methyl-l-nitrobenzene plus phenylacetone gives 2,7-diamino-3-phenyl-G-methylquinoxaline;

2-amino-3-nitroso-6-hydroxypyridine plus phenylacetone gives 2-amino-3-phenyl-7-hydroxypyridopyrazine.

What is claimed is:

1. A process for perapring a heterocyclic compound of the structure:

N NHQ- in which R is a member selected from the group consisting of lower alkyl, cyclohexyl, cyclopentyl, phenyl, thienyl, lower alkoxy, phenoxy and carbamyl; and X is a condensed aromatic residue which, when taken together with the two carbon atoms to which it is attached, is a member of the group consisting of phenylene, naphthylidene, pyrimidinediyl and pyridinediyl; comprising reacting an acylmethylene compound having a structure selected from the group consisting of:

in which R is a member selected from the group consisting of phenyl, lower alkyl, carbo-lower-alkoxy and lower alkoxy, and R is a member selected from the group consisting of thienyl, phenyl and carbamyl; and H R1-C(l3HR Py Z in which R is as described herebefore, R is a member selected from the group consisting of thienyl, phenyl, carbamyl, lower alkyl, phenoxy, lower alkoxy and cyclohexyl, Py is a pyridinium moiety and Z is an anion se lectedfrom the group consisting of bromide, chloride and iodide, with an o-nitrosoamine of the structure:

B No in which X is as defined herefore in the presence of cyanide ions.

o as 2. The process of claim 1 characterized in that X taken with the two carbon atoms to which it is attached is pyrimidinediyl.

3. The process of claim 1 characterized in that the reaction is run at from room temperature up to the reflux temperature of the reaction mixture and in an aqueous lower allranol solvent.

4. The process of claim 1 characterized in that X taken with the two carbon atoms to which it is attached is phenylene substituted by a minimum of one member selected from the group consisting of amino and hydroxyl.

5. The process of claim 1 characterized in that X taken with the two carbon atoms to which it is attached is pyridinediyl substituted by a minimum of one member selected from the group consisting of amino and hydroxyi.

6. A process for preparing a 4,7-diamino--pteridinecarboxarnide comprising reacting et-benzoylacetamide-epyridinium bromide with a 4,6diamino-5- nitrosopyrimidine in the presence of cyanide ions.

7. A process for preparing a 4,7-diarnino-6-pteridinecarboxamide comprising reacting benzoylacetarnide with a 4,6-diamino-5-nitrosopyrimidine in the presence of cyanide ions. I i '8. A process for preparing 4,7-diamino-2- phenyl-6- methylpteridine comprising reacting propiophenone-mpyridinium bromide with4,6-diamino-S-nitroso-Z-phenylpyrimidine in the presence of cyanide ions.

References Q'Jited in the file of this patent Timrnis; Nature, vol. 164 (19 49), p; 139. Osdene et al.: Chemistry and Industry (1954), pp. 4()46. 

6. A PROCESS FOR PREPARING A 4,7-DIAMINO-6-PTERIDINECARBOXAMIDE COMPRISING REACTING A-BENZOLYACETAMIDE-APYRIDINIUM BROMIDE WITH A 4,6-DIAMINO-5-NITROSOPYRIMIDINE IN THE PRESENCE OF CYANIDE IONS. 